Mechanisms of action of amyloid-beta and its precursor protein in neuronal cell death

• Published in: Metabolic brain disease 2020, Vol.35 (1), p.11-30
• Main Authors: Leong, Yong Qi, Ng, Khuen Yen, Chye, Soi Moi, Ling, Anna Pick Kiong, Koh, Rhun Yian
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Apoptosis; Autophagy; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell activation; Cell death; Cell Death - physiology; Humans; Metabolic Diseases; Metabolites; Mortality; Necroptosis; Necrosis; Neurodegenerative diseases; Neurofibrillary tangles; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Neurosciences; Neurotoxicity; Oncology; Peptides; Phagocytosis; Precursors; Proteins; Review Article; Senile plaques; Signal transduction; β-Amyloid
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-019-00516-y

Extracellular senile plaques and intracellular neurofibrillary tangles are the neuropathological findings of the Alzheimer’s disease (AD). Based on the amyloid cascade hypothesis, the main component of senile plaques, the amyloid-beta (Aβ) peptide, and its derivative called amyloid precursor protein (APP) both have been found to place their central roles in AD development for years. However, the recent therapeutics have yet to reverse or halt this disease. Previous evidence demonstrates that the accumulation of Aβ peptides and APP can exert neurotoxicity and ultimately neuronal cell death. Hence, we discuss the mechanisms of excessive production of Aβ peptides and APP serving as pathophysiologic stimuli for the initiation of various cell signalling pathways including apoptosis, necrosis, necroptosis and autophagy which lead to neuronal cell death. Conversely, the activation of such pathways could also result in the abnormal generation of APP and Aβ peptides. An elucidation of actions of APP and its metabolite, Aβ, could be vital in suggesting novel therapeutic opportunities.